{"gene":"LAMP1","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":1996,"finding":"The 11-amino acid cytoplasmic tail of LAMP1 contains a tyrosine-based YXXI sorting motif that is sufficient for lysosomal targeting. Mutants retaining only the RKR membrane anchor and YXXI motif still localize to dense lysosomes. However, deleting one amino acid or adding five amino acids to alter the spacing of the YXXI motif relative to the membrane almost completely abolishes lysosomal targeting, trapping LAMP1 in a recycling pathway between the plasma membrane and early endocytic compartments.","method":"Site-directed mutagenesis of cytoplasmic tail, pulse-chase kinetics, subcellular fractionation, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with kinetic trafficking assays in intact cells, rigorous mechanistic dissection of sorting signal spacing","pmids":["8647888"],"is_preprint":false},{"year":1996,"finding":"The tyrosine-based lysosomal targeting signal in the LAMP1 cytoplasmic tail mediates sorting into AP-1-positive clathrin-coated vesicles at the trans-Golgi network. The cytosolic domain of LAMP1 binds both AP-1 and AP-2 adaptors, and LAMP1 is present in AP-1-positive vesicles/tubules in the trans-Golgi region. AP-1 binding and localization to AP-1 CCVs require the functional tyrosine-based signal.","method":"Co-immunoprecipitation (cytosolic domain binding to AP-1/AP-2), immunogold electron microscopy, adaptor binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical binding assays plus ultrastructural localization, functional signal requirement demonstrated","pmids":["8895568"],"is_preprint":false},{"year":1992,"finding":"The majority of newly synthesized LAMP1 is directly transported from the trans-Golgi network to lysosomes (half-time ~60 min), bypassing the plasma membrane. A minor fraction (~minority) is first transported to the cell surface and then internalized to reach lysosomes via the endocytic pathway (half-time >2 h). After granulocytic differentiation, direct intracellular sorting becomes more efficient, leaving only a minute fraction at the cell surface.","method":"Pulse-chase metabolic labeling, cell surface biotinylation, Percoll density gradient fractionation","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (pulse-chase, biotinylation, density fractionation) in two cellular differentiation states","pmids":["1632650"],"is_preprint":false},{"year":1999,"finding":"Asparagine-linked oligosaccharides protect LAMP1 and LAMP2 from intracellular proteolysis within lysosomes. Removal of Asn-linked glycans from fully folded LAMP1 and LAMP2 in living cells using endoglycosidase H results in their rapid degradation, whereas the related LIMP-2 remains relatively stable. Depletion of both LAMPs had no measurable effect on endosomal/lysosomal pH, osmotic stability, or density, but delayed transport of endocytosed material to dense lysosomes.","method":"Endoglycosidase H treatment in live cells, pulse-chase degradation assays, pH and osmotic stability measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct enzymatic removal of glycans on folded protein in intact cells, multiple functional readouts","pmids":["10521503"],"is_preprint":false},{"year":1998,"finding":"Newly synthesized LAMP1 and LAMP2 are sorted at the trans-Golgi network into transport vesicles that are distinct from mannose-6-phosphate receptor/gamma-adaptin (AP-1 clathrin-coated) vesicles. LAMP vesicle generation required ATP, cytosol, was temperature-dependent and brefeldin A-sensitive. Wortmannin inhibited MPR/gamma-adaptin vesicle production but had no effect on LAMP vesicle generation, demonstrating separate TGN sorting pathways for LAMPs versus MPRs despite both using tyrosine-based motifs.","method":"In vitro TGN vesicle generation assay with tritiated CMP-sialic acid labeling, Nycodenz gradient sedimentation, wortmannin inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — cell-free reconstitution of vesicle budding combined with pharmacological inhibition and density gradient separation","pmids":["9668075"],"is_preprint":false},{"year":2004,"finding":"Newly synthesized LAMP1 traffics from the trans-Golgi network directly to early endosomes prior to delivery to late endosomes and lysosomes. Using a LAMP1 chimera (YAL) with tyrosine sulfation motifs fused to avidin, labeled chimera was captured by biotinylated probes endocytosed for only 5 min (early endosomes). In vitro fusion assays showed TGN-derived vesicles can fuse with early endosomes but not late endosomes or lysosomes.","method":"Novel LAMP1 chimera trafficking assay, in vitro TGN-to-endosome fusion reconstitution, biotinylated endocytic probe capture","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cell-free reconstitution complemented by in vivo chimera capture assay, rigorous kinetic design","pmids":["15296493"],"is_preprint":false},{"year":2013,"finding":"LAMP1/CD107a is required for efficient perforin delivery to lytic granules in NK cells. LAMP1 RNAi causes inhibition of NK-cell cytotoxicity, failure to deliver granzyme B to target cells, decreased perforin (but not granzyme B) levels in granules, and retention of perforin in trans-Golgi network-derived transport vesicles. Disruption of LAMP1's binding partner AP-1 sorting complex also causes perforin retention in transport vesicles, indicating that AP-1/LAMP1 interaction on transport vesicle surfaces is required for perforin trafficking to lytic granules.","method":"RNA interference (LAMP1 RNAi), immunofluorescence, cytotoxicity assays, granzyme B delivery assay, AP-1 disruption","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi loss-of-function with multiple mechanistic readouts (perforin/granzyme levels, granule movement, cytotoxicity), supported by AP-1 disruption epistasis","pmids":["23632890"],"is_preprint":false},{"year":2013,"finding":"Surface CD107a/LAMP1 protects NK cells from degranulation-associated self-destruction. Engineered surface expression of CD107a/LAMP1 (but not CD107b/LAMP2) reduces granule-mediated killing of transfected target cells and reduces perforin binding to cells; this protection depends on glycosylation of the CD107a/LAMP1 hinge. Knockdown of CD107a/LAMP1 in primary human NK cells and deficiency in mice results in increased NK cell apoptosis upon target cell-induced degranulation.","method":"Engineered surface expression constructs, glycosylation-deficient mutants, LAMP1 knockdown in primary NK cells, LAMP1-deficient mouse NK cells, perforin binding assay, apoptosis measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (gain-of-function, loss-of-function in primary cells and mice, glycosylation mutants, perforin binding), replicated across systems","pmids":["23847195"],"is_preprint":false},{"year":2005,"finding":"BLOC-3 (the HPS1/HPS4 complex) is required for optimal microtubule-dependent movement of LAMP1-containing late endocytic organelles. BLOC-3-deficient fibroblasts show reduced perinuclear clustering of LAMP1-positive organelles and a lower frequency of microtubule-dependent movement events (toward and away from the perinuclear region), without affecting duration or speed of individual movement events. LAMP1-GFP overexpression causes aberrant aggregation of late endocytic organelles dependent on LAMP1 dimerization via its cytoplasmic tail-GFP.","method":"Quantitative image analysis of organelle distribution, time-lapse fluorescence microscopy of LAMP1-GFP in live cells, comparison of WT vs. BLOC-3-deficient fibroblasts, dimerization mutant (LAMP1-mGFP)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with quantitative analysis and genetic mutant comparison, single lab but two orthogonal approaches","pmids":["16249233"],"is_preprint":false},{"year":2007,"finding":"LAMP1 and LAMP2 together are required for phagosome maturation and bacterial killing. In LAMP1/LAMP2 double-deficient fibroblasts, phagosomes containing Neisseria gonorrhoeae fail to acquire Rab7 and RILP, do not undergo dynein/dynactin-mediated centripetal movement, and remain peripheral, preventing bacterial killing. Single LAMP1- or LAMP2-deficient cells form phagosomes that gradually acquire microbicidal activity, indicating redundant functions.","method":"LAMP1/LAMP2 knockout mouse fibroblasts, siRNA knockdown, bacterial survival assay, Rab7/RILP recruitment immunofluorescence, microtubule transport analysis","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with siRNA, multiple molecular readouts (Rab7, RILP recruitment, organelle motility, bacterial killing)","pmids":["17506821"],"is_preprint":false},{"year":2000,"finding":"Increased cell-surface expression of LAMP1 (via mutation of the lysosomal targeting motif) renders CHO cells more susceptible to Trypanosoma cruzi invasion in a microtubule-dependent fashion, and enhances Ca2+-triggered lysosome exocytosis. Mutation of critical residues in the LAMP1 cytoplasmic tail lysosome-targeting motif abolishes both the invasion enhancement and the enhanced lysosome exocytosis, indicating that LAMP1 cytoplasmic tail interactions (not the luminal domain) modulate T. cruzi entry by promoting lysosome-plasma membrane fusion.","method":"Transfection of WT and cytoplasmic tail mutant LAMP1 into CHO cells, T. cruzi invasion assay, beta-hexosaminidase exocytosis assay, microtubule inhibitor treatment","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — gain-of-function with structure-function mutants, multiple functional readouts (invasion, exocytosis), mechanistic conclusion validated by tail mutations","pmids":["11207602"],"is_preprint":false},{"year":2012,"finding":"LAMP1 and LAMP2B are the most abundant interaction partners of the lysosomal polypeptide transporter TAPL (ABCB9), identified by proteomics. The interaction interface maps to the four-transmembrane N-terminal domain (TMD0) of TAPL; LAMP proteins bind TAPL independently. This interaction does not affect TAPL subcellular localization or peptide transport activity, but in LAMP-deficient cells TAPL half-life is reduced 5-fold due to increased lysosomal degradation, indicating LAMP proteins retain TAPL on the limiting membrane and prevent its sorting to intraluminal vesicles.","method":"Proteomic interactome, co-immunoprecipitation, domain mapping, LAMP-deficient cells, half-life measurements","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP with domain mapping, loss-of-function in LAMP-deficient cells with quantitative stability measurement","pmids":["22641697"],"is_preprint":false},{"year":2016,"finding":"LAMP1 and LAMP2 subdomains adopt a unique β-prism fold (confirmed by structural analysis, consistent with DC-LAMP/LAMP3). The N-domain of LAMP1 is necessary for multimeric assembly of LAMPs, whereas the N-domain of LAMP2 is repressive for such assembly, revealing distinct assembly modes for LAMP1 versus LAMP2 that may underlie their different functions.","method":"Structural analysis (β-prism fold determination), immunoprecipitation-based N-domain truncation analysis of LAMP multimerization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — structural fold identification plus Co-IP domain truncation experiments, single lab","pmids":["27663661"],"is_preprint":false},{"year":1995,"finding":"LAMP1 biosynthetic transport in rat hepatocytes proceeds via multiple convergence points with the endocytic pathway: a major direct intracellular route to late endosomes (t1/2 = 45 min) then lysosomes (t1/2 = 85 min); a minor peripheral route via early endosomes (t1/2 = 33 min) and cell surface (t1/2 = 32 min); and a retrograde delivery from late endosomes back to early endosomes before final lysosomal delivery.","method":"Pulse-chase metabolic labeling with kinetic analysis, subcellular fractionation into endosomal compartments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase with subcellular fractionation, single lab, quantitative kinetics but indirect compartment assignment","pmids":["7556456"],"is_preprint":false},{"year":1990,"finding":"LAMP1 is present on the surface of activated but not resting human platelets, co-localizing with the lysosomal enzyme beta-galactosidase (but not with alpha- or dense granule markers) by sucrose density gradient fractionation. Half-maximal surface expression is induced by thrombin concentrations that trigger lysosomal enzyme release, indicating LAMP1 surface exposure specifically marks lysosomal secretion upon platelet activation.","method":"Sucrose density gradient granule fractionation, co-localization with lysosomal enzyme beta-galactosidase, flow cytometry surface expression after agonist stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation with lysosomal marker co-localization and functional correlation with degranulation, single lab","pmids":["2211717"],"is_preprint":false},{"year":2001,"finding":"Neisseria pili induce a transient cytosolic Ca2+ flux in human epithelial cells that triggers lysosome exocytosis, rapidly redistributing LAMP1 from intracellular lysosomes to the cell surface, where it is cleaved by Neisseria IgA1 protease. Surface LAMP1 accessibility is thus controlled by Ca2+-regulated lysosomal exocytosis.","method":"Ca2+ flux measurement, lysosome exocytosis assay, LAMP1 surface redistribution immunofluorescence, IgA1 protease cleavage assay","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic steps (Ca2+ flux, exocytosis, surface redistribution, protease cleavage) linked in single study, single lab","pmids":["11298650"],"is_preprint":false},{"year":2002,"finding":"Neisseria porin P1.B induces a Ca2+ flux in epithelial cells that stimulates exocytosis of early and late endosomes (not lysosomes), increasing LAMP1 on the cell surface by a mechanism distinct from pilus-induced lysosome exocytosis. This represents a separate Ca2+-dependent exocytic route that delivers LAMP1 to the plasma membrane for IgA1 protease cleavage.","method":"Ca2+ flux measurement, differential exocytosis assays (early/late endosome vs lysosome markers), LAMP1 surface measurement by flow cytometry","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of two distinct exocytic pathways, single lab, multiple organelle markers","pmids":["12379671"],"is_preprint":false},{"year":2004,"finding":"Soluble LAMP1 carrying the cytoplasmic tail [LAMP1(+Tail)] in circulation aggregates and interacts with plasma proteins. Transthyretin, isolated by affinity chromatography with either recombinant LAMP1(-Tail) or a synthesized 14-amino acid LAMP1 cytoplasmic tail peptide, interacts specifically with the LAMP1 cytoplasmic tail. Only the tail-containing form aggregates, suggesting transthyretin (a homotetramer) may crosslink soluble LAMP1.","method":"Affinity chromatography, immunoassay quantification of LAMP1 forms, recombinant protein production","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — affinity chromatography with synthetic tail peptide and two recombinant forms, single lab","pmids":["15200388"],"is_preprint":false},{"year":2016,"finding":"LAMP1 serves as a critical endosomal receptor for Lassa virus (LASV) at acidic pH. A crystal structure of LASV GP1 identified a unique histidine triad forming the LAMP1 binding site; mutation of this triad impairs LAMP1 recognition and reduces infectivity. LAMP1 binding promotes membrane fusion, and His230 of LAMP1 is required to engage the spike complex. The histidines also sense acidic pH, preventing premature spike triggering.","method":"X-ray crystallography of LASV GP1, site-directed mutagenesis of histidine triad, LAMP1 binding assays, infectivity assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure combined with mutagenesis of both viral and host binding determinants with functional readouts","pmids":["25972533"],"is_preprint":false},{"year":2018,"finding":"LAMP1 increases the efficiency of Lassa virus (LASV) infection by elevating the pH threshold for GPC-mediated fusion, enabling LASV to fuse in less acidic endosomal compartments. In wild-type (LAMP1+) cells, LASV entry occurs through less acidic endosomes than in LAMP1 KO cells. LAMP1 is not absolutely required for LASV fusion but substantially increases its efficiency by allowing viral exit from endosomes before encountering more acidic/proteolytic environments.","method":"LAMP1 knockout cells, cell-cell and pseudovirus-cell surface fusion assays, pH threshold measurement, endosomal pH monitoring","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — LAMP1 KO cells combined with quantitative fusion assays and pH measurements, two orthogonal fusion systems","pmids":["29295909"],"is_preprint":false},{"year":2022,"finding":"Human LAMP1 accelerates the kinetics of Lassa virus small fusion pore formation and potently promotes fusion pore dilation. The soluble LAMP1 ectodomain accelerates nascent pore formation but fails to promote efficient pore dilation, whereas ectopic full-length hLAMP1 dramatically promotes both initial and full dilation of fusion pores in forced plasma membrane fusion assays, implicating the LAMP1 transmembrane domain in this late stage of LASV fusion.","method":"Single virus imaging, population-based fusion assays, pseudovirus and VLP systems, ectopic hLAMP1 expression, forced plasma membrane fusion at low pH, soluble ectodomain vs. full-length comparison","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal fusion assay systems, single virus imaging plus population assays, domain dissection (ectodomain vs. transmembrane)","pmids":["35969633"],"is_preprint":false},{"year":2016,"finding":"A small molecule inhibitor of Lassa fever virus entry targets LAMP1 directly (identified by photo-reactive probe cross-linking). LAMP1 binding to LASV glycoprotein is cholesterol-dependent; the inhibitor blocks infection by competing with cholesterol in LAMP1. Mutational analysis of a docking model identified a putative inhibitor binding site within the cholesterol-binding pocket of the LAMP1 domain that engages GP.","method":"Photo-reactive probe cross-linking to identify LAMP1 as drug target, cholesterol dependence biochemical assays, mutational analysis of LAMP1 cholesterol-binding pocket, docking model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — photo-crosslinking target identification plus mutational analysis, single lab, docking is computational but supported by experimental data","pmids":["30265711"],"is_preprint":false},{"year":2011,"finding":"Salmonella acquires LAMP1 on phagosomes through a mechanism involving the bacterial effector SipC binding specifically to host Syntaxin6 via its C terminus, recruiting Syntaxin6 and accessory molecules (VAMP2, Rab6, Rab8) to Salmonella-containing phagosomes (SCP) to enable fusion with LAMP1-containing Golgi-derived vesicles. sipC knockout or sipC(M398K) mutant SCPs fail to recruit Syntaxin6 or acquire LAMP1. shRNA depletion of Syntaxin6 in macrophages significantly inhibits LAMP1 recruitment on SCP.","method":"Co-immunoprecipitation (SipC-Syntaxin6 interaction), bacterial mutants (sipC KO and point mutant), shRNA knockdown of Syntaxin6, immunofluorescence of LAMP1/Syntaxin6 recruitment, mouse infection model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus multiple genetic tools (bacterial KO, point mutant, host shRNA), in vivo validation","pmids":["22190682"],"is_preprint":false},{"year":2019,"finding":"UBL4A causes lysosomal dysfunction by directly interacting with LAMP1, impairing autophagic degradation in pancreatic cancer cells. Co-immunoprecipitation confirmed physical interaction between UBL4A and LAMP1. LAMP1 overexpression reversed the antitumor (autophagy-inhibiting) effects of UBL4A, placing LAMP1 downstream of UBL4A in regulating lysosomal function and autophagic flux.","method":"Co-immunoprecipitation (UBL4A-LAMP1 interaction), LAMP1 overexpression rescue, Western blotting for autophagic flux markers","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP interaction plus epistasis rescue experiment, single lab","pmids":["31288830"],"is_preprint":false},{"year":2019,"finding":"SIRT1-mediated deacetylation of a lysine residue on the cytoplasmic domain of LAMP1 drives lipophagy and senescence in prostate cancer cells. AGG treatment induces cytoplasmic SIRT1, which deacetylates LAMP1's cytoplasmic domain, resulting in lipophagy-mediated free fatty acid accumulation and ROS generation that promotes senescence.","method":"SIRT1 inhibitor (sirtinol) treatment, mechanistic pathway experiments linking SIRT1 to LAMP1 deacetylation, lipophagy assays, ROS measurement","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — post-translational modification inference from inhibitor data without direct deacetylation site confirmation by mutagenesis in this abstract","pmids":["31544977"],"is_preprint":false},{"year":2016,"finding":"Fucosylation of LAMP1 and LAMP2 by FUT1 (but not FUT2) regulates lysosomal positioning and autophagic flux in breast cancer cells. FUT1 knockdown causes LAMP1/LAMP2 to shift from peripheral to perinuclear distribution; this perinuclear positioning is correlated with decreased mTORC1 activity, increased autophagosome-lysosome fusion, and enhanced autophagic flux. LAMP1 and LAMP2 are confirmed substrates for FUT1 by targeted nanoLC-MS3 and MALDI-TOF analysis.","method":"FUT1 knockdown, targeted nanoLC-MS3 glycan analysis, MALDI-TOF, subcellular localization by imaging, mTORC1 activity measurement, autophagic flux assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed glycan modification combined with loss-of-function and multiple functional readouts, single lab","pmids":["27560716"],"is_preprint":false},{"year":1999,"finding":"In Pompe disease (lysosomal glycogen storage disorder) fibroblasts, LAMP1 glycoprocessing is retarded (t1/2 = 25 min vs. 17 min in controls) and trafficking to lysosomes is markedly delayed (t1/2 = 200 min vs. 100 min). A proportion of newly synthesized LAMP1 (5-8%) is trafficked out of cells; the extracellular soluble form lacks the cytoplasmic tail, whereas a soluble lysosomal pool also lacks the tail, suggesting clipping from the membrane. LAMP1 turnover is slower in Pompe cells (t1/2 = 4.9 days vs. 1.6 days in controls).","method":"Pulse-chase metabolic labeling, subcellular fractionation, turnover assays, tail-domain characterization of extracellular LAMP1 forms","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative pulse-chase kinetics in disease vs. control fibroblasts, multiple trafficking readouts, single lab","pmids":["10066386"],"is_preprint":false},{"year":1994,"finding":"Galectin-1 binds to LAMP1 (lysosome-associated membrane glycoprotein-1) as one of its major endogenous ligands in colon carcinoma cells, demonstrated by affinity chromatography of radiolabeled cell extracts on immobilized galectin-1 followed by immunoprecipitation from lactose-eluted material.","method":"Affinity chromatography on immobilized galectin-1, immunoprecipitation from lactose eluate, [3H]glucosamine radiolabeling","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity chromatography with specificity control (lactose elution), single lab","pmids":["7954433"],"is_preprint":false},{"year":2015,"finding":"Cell surface LAMP1 on high-metastatic B16F10 melanoma cells facilitates lung metastasis primarily through its polyLacNAc (poly-N-acetyllactosamine) carbohydrates that bind galectin-3. LAMP1 is the major carrier of polyLacNAc on these cells. shRNA-mediated LAMP1 knockdown decreases surface LAMP1, reduces galectin-3 binding to cell surface, impairs spreading and motility on galectin-3, and significantly reduces experimental lung metastasis. Overexpression of a mutant LAMP1 (Y386A) with low polyLacNAc fails to augment galectin-3 binding or lung metastasis.","method":"shRNA inducible knockdown, lentiviral mutant overexpression, flow cytometry, experimental lung metastasis assay, galectin-3 binding assay, spreading/motility on ECM components","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with carbohydrate-deficient mutant, in vivo metastasis readout, single lab","pmids":["25614122"],"is_preprint":false},{"year":2015,"finding":"Extracellular galectin-3 induces MMP9 expression via p38 MAPK pathway signaling through cell-surface LAMP1. LAMP1 is identified as the key mediator because shRNA knockdown of LAMP1 (which is the major carrier of polyLacNAc, the galectin-3 ligand) abolishes galectin-3-induced MMP9 upregulation via p38 MAPK.","method":"shRNA knockdown of LAMP1, signaling pathway inhibitors, RT-PCR/Western blot for MMP9","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — shRNA with pharmacological inhibitors placing LAMP1 in p38 MAPK signaling pathway, single lab","pmids":["25739356"],"is_preprint":false},{"year":2022,"finding":"Drosophila Lamp1 is a bona fide ortholog of vertebrate LAMP1/LAMP2 but, unlike lamp1/lamp2 double-mutant mice, Lamp1-deficient flies are viable and do not show autophagy defects. However, Lamp1 deficiency increases the number of acidic organelles and causes defects in lipid metabolism, with elevated sterols and diacylglycerols, indicating a role for LAMP1 in lipid transport rather than autophagy in Drosophila.","method":"Drosophila Lamp1 mutant characterization, autophagy assays (LC3/Atg8a puncta, autophagic vacuoles), acidic organelle quantification (LysoTracker), lipid profiling","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal readouts in Drosophila model; divergence from mammalian function noted","pmids":["35266854"],"is_preprint":false}],"current_model":"LAMP1 is a heavily N-glycosylated type I lysosomal membrane protein whose cytoplasmic YXXI tyrosine-based sorting motif mediates TGN-to-early endosome trafficking via AP-1 and AP-2 clathrin adaptors, with the spacing of this motif relative to the membrane being critical for proper sorting; its luminal Asn-linked glycans protect the polypeptide from lysosomal proteolysis; at the lysosomal membrane it stabilizes the polypeptide transporter TAPL and, in NK cells, is required for perforin trafficking to lytic granules (via AP-1 interaction) and for protection of NK cells from degranulation-associated self-damage through glycosylation-dependent suppression of perforin binding; LAMP1 also marks Ca2+-regulated lysosomal exocytosis (as seen in platelets, NK cells, and T. cruzi invasion), and at the cell surface its polyLacNAc carbohydrates engage galectin-3 to promote melanoma lung metastasis via p38 MAPK/MMP9 signaling; as a viral receptor, LAMP1's luminal domain (via a histidine-230 residue and a cholesterol-binding pocket) engages the Lassa virus GP1 histidine triad at acidic endosomal pH to elevate the pH threshold for membrane fusion and promote fusion pore dilation through its transmembrane domain."},"narrative":{"mechanistic_narrative":"Parse failed — see logs","teleology":[],"mechanism_profile":null},"prefetch_data":{"uniprot":{"accession":"P11279","full_name":"Lysosome-associated membrane glycoprotein 1","aliases":["CD107 antigen-like family member A"],"length_aa":417,"mass_kda":44.9,"function":"Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, lysosomal pH regulation, autophagy and cholesterol homeostasis (PubMed:37390818). Acts as an important regulator of lysosomal lumen pH regulation by acting as a direct inhibitor of the proton channel TMEM175, facilitating lysosomal acidification for optimal hydrolase activity (PubMed:37390818). Also plays an important role in NK-cells cytotoxicity (PubMed:2022921, PubMed:23632890). Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule (PubMed:23632890). In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content (PubMed:23847195). Presents carbohydrate ligands to selectins (PubMed:7685349) (Microbial infection) Acts as a receptor for Lassa virus glycoprotein (PubMed:24970085, PubMed:25972533, PubMed:27605678, PubMed:28448640). Also promotes fusion of the virus with host membrane in less acidic endosomes (PubMed:29295909) (Microbial infection) Supports the FURIN-mediated cleavage of mumps virus fusion protein F by interacting with both FURIN and the unprocessed form but not the processed form of the viral protein F","subcellular_location":"Lysosome membrane; Endosome membrane; Late endosome membrane; Cell membrane; Cytolytic granule membrane","url":"https://www.uniprot.org/uniprotkb/P11279/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAMP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000185896","cell_line_id":"CID000888","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"RAB7A","stoichiometry":10.0},{"gene":"SLC18B1","stoichiometry":10.0},{"gene":"CLASP1","stoichiometry":4.0},{"gene":"SLC2A8","stoichiometry":4.0},{"gene":"VAMP3;VAMP2","stoichiometry":4.0},{"gene":"RAB2A","stoichiometry":4.0},{"gene":"LAMTOR3","stoichiometry":4.0},{"gene":"ARL8B","stoichiometry":4.0},{"gene":"LAMTOR1","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000888","total_profiled":1310},"omim":[{"mim_id":"620778","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, SHORT CYTOPLASMIC TAIL, 1; 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YXXI sorting motif that is sufficient for lysosomal targeting. Mutants retaining only the RKR membrane anchor and YXXI motif still localize to dense lysosomes. However, deleting one amino acid or adding five amino acids to alter the spacing of the YXXI motif relative to the membrane almost completely abolishes lysosomal targeting, trapping LAMP1 in a recycling pathway between the plasma membrane and early endocytic compartments.\",\n      \"method\": \"Site-directed mutagenesis of cytoplasmic tail, pulse-chase kinetics, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with kinetic trafficking assays in intact cells, rigorous mechanistic dissection of sorting signal spacing\",\n      \"pmids\": [\"8647888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The tyrosine-based lysosomal targeting signal in the LAMP1 cytoplasmic tail mediates sorting into AP-1-positive clathrin-coated vesicles at the trans-Golgi network. The cytosolic domain of LAMP1 binds both AP-1 and AP-2 adaptors, and LAMP1 is present in AP-1-positive vesicles/tubules in the trans-Golgi region. AP-1 binding and localization to AP-1 CCVs require the functional tyrosine-based signal.\",\n      \"method\": \"Co-immunoprecipitation (cytosolic domain binding to AP-1/AP-2), immunogold electron microscopy, adaptor binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical binding assays plus ultrastructural localization, functional signal requirement demonstrated\",\n      \"pmids\": [\"8895568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The majority of newly synthesized LAMP1 is directly transported from the trans-Golgi network to lysosomes (half-time ~60 min), bypassing the plasma membrane. A minor fraction (~minority) is first transported to the cell surface and then internalized to reach lysosomes via the endocytic pathway (half-time >2 h). After granulocytic differentiation, direct intracellular sorting becomes more efficient, leaving only a minute fraction at the cell surface.\",\n      \"method\": \"Pulse-chase metabolic labeling, cell surface biotinylation, Percoll density gradient fractionation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (pulse-chase, biotinylation, density fractionation) in two cellular differentiation states\",\n      \"pmids\": [\"1632650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Asparagine-linked oligosaccharides protect LAMP1 and LAMP2 from intracellular proteolysis within lysosomes. Removal of Asn-linked glycans from fully folded LAMP1 and LAMP2 in living cells using endoglycosidase H results in their rapid degradation, whereas the related LIMP-2 remains relatively stable. Depletion of both LAMPs had no measurable effect on endosomal/lysosomal pH, osmotic stability, or density, but delayed transport of endocytosed material to dense lysosomes.\",\n      \"method\": \"Endoglycosidase H treatment in live cells, pulse-chase degradation assays, pH and osmotic stability measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct enzymatic removal of glycans on folded protein in intact cells, multiple functional readouts\",\n      \"pmids\": [\"10521503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Newly synthesized LAMP1 and LAMP2 are sorted at the trans-Golgi network into transport vesicles that are distinct from mannose-6-phosphate receptor/gamma-adaptin (AP-1 clathrin-coated) vesicles. LAMP vesicle generation required ATP, cytosol, was temperature-dependent and brefeldin A-sensitive. Wortmannin inhibited MPR/gamma-adaptin vesicle production but had no effect on LAMP vesicle generation, demonstrating separate TGN sorting pathways for LAMPs versus MPRs despite both using tyrosine-based motifs.\",\n      \"method\": \"In vitro TGN vesicle generation assay with tritiated CMP-sialic acid labeling, Nycodenz gradient sedimentation, wortmannin inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cell-free reconstitution of vesicle budding combined with pharmacological inhibition and density gradient separation\",\n      \"pmids\": [\"9668075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Newly synthesized LAMP1 traffics from the trans-Golgi network directly to early endosomes prior to delivery to late endosomes and lysosomes. Using a LAMP1 chimera (YAL) with tyrosine sulfation motifs fused to avidin, labeled chimera was captured by biotinylated probes endocytosed for only 5 min (early endosomes). In vitro fusion assays showed TGN-derived vesicles can fuse with early endosomes but not late endosomes or lysosomes.\",\n      \"method\": \"Novel LAMP1 chimera trafficking assay, in vitro TGN-to-endosome fusion reconstitution, biotinylated endocytic probe capture\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cell-free reconstitution complemented by in vivo chimera capture assay, rigorous kinetic design\",\n      \"pmids\": [\"15296493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LAMP1/CD107a is required for efficient perforin delivery to lytic granules in NK cells. LAMP1 RNAi causes inhibition of NK-cell cytotoxicity, failure to deliver granzyme B to target cells, decreased perforin (but not granzyme B) levels in granules, and retention of perforin in trans-Golgi network-derived transport vesicles. Disruption of LAMP1's binding partner AP-1 sorting complex also causes perforin retention in transport vesicles, indicating that AP-1/LAMP1 interaction on transport vesicle surfaces is required for perforin trafficking to lytic granules.\",\n      \"method\": \"RNA interference (LAMP1 RNAi), immunofluorescence, cytotoxicity assays, granzyme B delivery assay, AP-1 disruption\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi loss-of-function with multiple mechanistic readouts (perforin/granzyme levels, granule movement, cytotoxicity), supported by AP-1 disruption epistasis\",\n      \"pmids\": [\"23632890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Surface CD107a/LAMP1 protects NK cells from degranulation-associated self-destruction. Engineered surface expression of CD107a/LAMP1 (but not CD107b/LAMP2) reduces granule-mediated killing of transfected target cells and reduces perforin binding to cells; this protection depends on glycosylation of the CD107a/LAMP1 hinge. Knockdown of CD107a/LAMP1 in primary human NK cells and deficiency in mice results in increased NK cell apoptosis upon target cell-induced degranulation.\",\n      \"method\": \"Engineered surface expression constructs, glycosylation-deficient mutants, LAMP1 knockdown in primary NK cells, LAMP1-deficient mouse NK cells, perforin binding assay, apoptosis measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (gain-of-function, loss-of-function in primary cells and mice, glycosylation mutants, perforin binding), replicated across systems\",\n      \"pmids\": [\"23847195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BLOC-3 (the HPS1/HPS4 complex) is required for optimal microtubule-dependent movement of LAMP1-containing late endocytic organelles. BLOC-3-deficient fibroblasts show reduced perinuclear clustering of LAMP1-positive organelles and a lower frequency of microtubule-dependent movement events (toward and away from the perinuclear region), without affecting duration or speed of individual movement events. LAMP1-GFP overexpression causes aberrant aggregation of late endocytic organelles dependent on LAMP1 dimerization via its cytoplasmic tail-GFP.\",\n      \"method\": \"Quantitative image analysis of organelle distribution, time-lapse fluorescence microscopy of LAMP1-GFP in live cells, comparison of WT vs. BLOC-3-deficient fibroblasts, dimerization mutant (LAMP1-mGFP)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with quantitative analysis and genetic mutant comparison, single lab but two orthogonal approaches\",\n      \"pmids\": [\"16249233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LAMP1 and LAMP2 together are required for phagosome maturation and bacterial killing. In LAMP1/LAMP2 double-deficient fibroblasts, phagosomes containing Neisseria gonorrhoeae fail to acquire Rab7 and RILP, do not undergo dynein/dynactin-mediated centripetal movement, and remain peripheral, preventing bacterial killing. Single LAMP1- or LAMP2-deficient cells form phagosomes that gradually acquire microbicidal activity, indicating redundant functions.\",\n      \"method\": \"LAMP1/LAMP2 knockout mouse fibroblasts, siRNA knockdown, bacterial survival assay, Rab7/RILP recruitment immunofluorescence, microtubule transport analysis\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with siRNA, multiple molecular readouts (Rab7, RILP recruitment, organelle motility, bacterial killing)\",\n      \"pmids\": [\"17506821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Increased cell-surface expression of LAMP1 (via mutation of the lysosomal targeting motif) renders CHO cells more susceptible to Trypanosoma cruzi invasion in a microtubule-dependent fashion, and enhances Ca2+-triggered lysosome exocytosis. Mutation of critical residues in the LAMP1 cytoplasmic tail lysosome-targeting motif abolishes both the invasion enhancement and the enhanced lysosome exocytosis, indicating that LAMP1 cytoplasmic tail interactions (not the luminal domain) modulate T. cruzi entry by promoting lysosome-plasma membrane fusion.\",\n      \"method\": \"Transfection of WT and cytoplasmic tail mutant LAMP1 into CHO cells, T. cruzi invasion assay, beta-hexosaminidase exocytosis assay, microtubule inhibitor treatment\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — gain-of-function with structure-function mutants, multiple functional readouts (invasion, exocytosis), mechanistic conclusion validated by tail mutations\",\n      \"pmids\": [\"11207602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LAMP1 and LAMP2B are the most abundant interaction partners of the lysosomal polypeptide transporter TAPL (ABCB9), identified by proteomics. The interaction interface maps to the four-transmembrane N-terminal domain (TMD0) of TAPL; LAMP proteins bind TAPL independently. This interaction does not affect TAPL subcellular localization or peptide transport activity, but in LAMP-deficient cells TAPL half-life is reduced 5-fold due to increased lysosomal degradation, indicating LAMP proteins retain TAPL on the limiting membrane and prevent its sorting to intraluminal vesicles.\",\n      \"method\": \"Proteomic interactome, co-immunoprecipitation, domain mapping, LAMP-deficient cells, half-life measurements\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP with domain mapping, loss-of-function in LAMP-deficient cells with quantitative stability measurement\",\n      \"pmids\": [\"22641697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LAMP1 and LAMP2 subdomains adopt a unique β-prism fold (confirmed by structural analysis, consistent with DC-LAMP/LAMP3). The N-domain of LAMP1 is necessary for multimeric assembly of LAMPs, whereas the N-domain of LAMP2 is repressive for such assembly, revealing distinct assembly modes for LAMP1 versus LAMP2 that may underlie their different functions.\",\n      \"method\": \"Structural analysis (β-prism fold determination), immunoprecipitation-based N-domain truncation analysis of LAMP multimerization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — structural fold identification plus Co-IP domain truncation experiments, single lab\",\n      \"pmids\": [\"27663661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"LAMP1 biosynthetic transport in rat hepatocytes proceeds via multiple convergence points with the endocytic pathway: a major direct intracellular route to late endosomes (t1/2 = 45 min) then lysosomes (t1/2 = 85 min); a minor peripheral route via early endosomes (t1/2 = 33 min) and cell surface (t1/2 = 32 min); and a retrograde delivery from late endosomes back to early endosomes before final lysosomal delivery.\",\n      \"method\": \"Pulse-chase metabolic labeling with kinetic analysis, subcellular fractionation into endosomal compartments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase with subcellular fractionation, single lab, quantitative kinetics but indirect compartment assignment\",\n      \"pmids\": [\"7556456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"LAMP1 is present on the surface of activated but not resting human platelets, co-localizing with the lysosomal enzyme beta-galactosidase (but not with alpha- or dense granule markers) by sucrose density gradient fractionation. Half-maximal surface expression is induced by thrombin concentrations that trigger lysosomal enzyme release, indicating LAMP1 surface exposure specifically marks lysosomal secretion upon platelet activation.\",\n      \"method\": \"Sucrose density gradient granule fractionation, co-localization with lysosomal enzyme beta-galactosidase, flow cytometry surface expression after agonist stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation with lysosomal marker co-localization and functional correlation with degranulation, single lab\",\n      \"pmids\": [\"2211717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neisseria pili induce a transient cytosolic Ca2+ flux in human epithelial cells that triggers lysosome exocytosis, rapidly redistributing LAMP1 from intracellular lysosomes to the cell surface, where it is cleaved by Neisseria IgA1 protease. Surface LAMP1 accessibility is thus controlled by Ca2+-regulated lysosomal exocytosis.\",\n      \"method\": \"Ca2+ flux measurement, lysosome exocytosis assay, LAMP1 surface redistribution immunofluorescence, IgA1 protease cleavage assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic steps (Ca2+ flux, exocytosis, surface redistribution, protease cleavage) linked in single study, single lab\",\n      \"pmids\": [\"11298650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Neisseria porin P1.B induces a Ca2+ flux in epithelial cells that stimulates exocytosis of early and late endosomes (not lysosomes), increasing LAMP1 on the cell surface by a mechanism distinct from pilus-induced lysosome exocytosis. This represents a separate Ca2+-dependent exocytic route that delivers LAMP1 to the plasma membrane for IgA1 protease cleavage.\",\n      \"method\": \"Ca2+ flux measurement, differential exocytosis assays (early/late endosome vs lysosome markers), LAMP1 surface measurement by flow cytometry\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of two distinct exocytic pathways, single lab, multiple organelle markers\",\n      \"pmids\": [\"12379671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Soluble LAMP1 carrying the cytoplasmic tail [LAMP1(+Tail)] in circulation aggregates and interacts with plasma proteins. Transthyretin, isolated by affinity chromatography with either recombinant LAMP1(-Tail) or a synthesized 14-amino acid LAMP1 cytoplasmic tail peptide, interacts specifically with the LAMP1 cytoplasmic tail. Only the tail-containing form aggregates, suggesting transthyretin (a homotetramer) may crosslink soluble LAMP1.\",\n      \"method\": \"Affinity chromatography, immunoassay quantification of LAMP1 forms, recombinant protein production\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — affinity chromatography with synthetic tail peptide and two recombinant forms, single lab\",\n      \"pmids\": [\"15200388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LAMP1 serves as a critical endosomal receptor for Lassa virus (LASV) at acidic pH. A crystal structure of LASV GP1 identified a unique histidine triad forming the LAMP1 binding site; mutation of this triad impairs LAMP1 recognition and reduces infectivity. LAMP1 binding promotes membrane fusion, and His230 of LAMP1 is required to engage the spike complex. The histidines also sense acidic pH, preventing premature spike triggering.\",\n      \"method\": \"X-ray crystallography of LASV GP1, site-directed mutagenesis of histidine triad, LAMP1 binding assays, infectivity assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure combined with mutagenesis of both viral and host binding determinants with functional readouts\",\n      \"pmids\": [\"25972533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LAMP1 increases the efficiency of Lassa virus (LASV) infection by elevating the pH threshold for GPC-mediated fusion, enabling LASV to fuse in less acidic endosomal compartments. In wild-type (LAMP1+) cells, LASV entry occurs through less acidic endosomes than in LAMP1 KO cells. LAMP1 is not absolutely required for LASV fusion but substantially increases its efficiency by allowing viral exit from endosomes before encountering more acidic/proteolytic environments.\",\n      \"method\": \"LAMP1 knockout cells, cell-cell and pseudovirus-cell surface fusion assays, pH threshold measurement, endosomal pH monitoring\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — LAMP1 KO cells combined with quantitative fusion assays and pH measurements, two orthogonal fusion systems\",\n      \"pmids\": [\"29295909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human LAMP1 accelerates the kinetics of Lassa virus small fusion pore formation and potently promotes fusion pore dilation. The soluble LAMP1 ectodomain accelerates nascent pore formation but fails to promote efficient pore dilation, whereas ectopic full-length hLAMP1 dramatically promotes both initial and full dilation of fusion pores in forced plasma membrane fusion assays, implicating the LAMP1 transmembrane domain in this late stage of LASV fusion.\",\n      \"method\": \"Single virus imaging, population-based fusion assays, pseudovirus and VLP systems, ectopic hLAMP1 expression, forced plasma membrane fusion at low pH, soluble ectodomain vs. full-length comparison\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal fusion assay systems, single virus imaging plus population assays, domain dissection (ectodomain vs. transmembrane)\",\n      \"pmids\": [\"35969633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A small molecule inhibitor of Lassa fever virus entry targets LAMP1 directly (identified by photo-reactive probe cross-linking). LAMP1 binding to LASV glycoprotein is cholesterol-dependent; the inhibitor blocks infection by competing with cholesterol in LAMP1. Mutational analysis of a docking model identified a putative inhibitor binding site within the cholesterol-binding pocket of the LAMP1 domain that engages GP.\",\n      \"method\": \"Photo-reactive probe cross-linking to identify LAMP1 as drug target, cholesterol dependence biochemical assays, mutational analysis of LAMP1 cholesterol-binding pocket, docking model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — photo-crosslinking target identification plus mutational analysis, single lab, docking is computational but supported by experimental data\",\n      \"pmids\": [\"30265711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Salmonella acquires LAMP1 on phagosomes through a mechanism involving the bacterial effector SipC binding specifically to host Syntaxin6 via its C terminus, recruiting Syntaxin6 and accessory molecules (VAMP2, Rab6, Rab8) to Salmonella-containing phagosomes (SCP) to enable fusion with LAMP1-containing Golgi-derived vesicles. sipC knockout or sipC(M398K) mutant SCPs fail to recruit Syntaxin6 or acquire LAMP1. shRNA depletion of Syntaxin6 in macrophages significantly inhibits LAMP1 recruitment on SCP.\",\n      \"method\": \"Co-immunoprecipitation (SipC-Syntaxin6 interaction), bacterial mutants (sipC KO and point mutant), shRNA knockdown of Syntaxin6, immunofluorescence of LAMP1/Syntaxin6 recruitment, mouse infection model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus multiple genetic tools (bacterial KO, point mutant, host shRNA), in vivo validation\",\n      \"pmids\": [\"22190682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBL4A causes lysosomal dysfunction by directly interacting with LAMP1, impairing autophagic degradation in pancreatic cancer cells. Co-immunoprecipitation confirmed physical interaction between UBL4A and LAMP1. LAMP1 overexpression reversed the antitumor (autophagy-inhibiting) effects of UBL4A, placing LAMP1 downstream of UBL4A in regulating lysosomal function and autophagic flux.\",\n      \"method\": \"Co-immunoprecipitation (UBL4A-LAMP1 interaction), LAMP1 overexpression rescue, Western blotting for autophagic flux markers\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP interaction plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"31288830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1-mediated deacetylation of a lysine residue on the cytoplasmic domain of LAMP1 drives lipophagy and senescence in prostate cancer cells. AGG treatment induces cytoplasmic SIRT1, which deacetylates LAMP1's cytoplasmic domain, resulting in lipophagy-mediated free fatty acid accumulation and ROS generation that promotes senescence.\",\n      \"method\": \"SIRT1 inhibitor (sirtinol) treatment, mechanistic pathway experiments linking SIRT1 to LAMP1 deacetylation, lipophagy assays, ROS measurement\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — post-translational modification inference from inhibitor data without direct deacetylation site confirmation by mutagenesis in this abstract\",\n      \"pmids\": [\"31544977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fucosylation of LAMP1 and LAMP2 by FUT1 (but not FUT2) regulates lysosomal positioning and autophagic flux in breast cancer cells. FUT1 knockdown causes LAMP1/LAMP2 to shift from peripheral to perinuclear distribution; this perinuclear positioning is correlated with decreased mTORC1 activity, increased autophagosome-lysosome fusion, and enhanced autophagic flux. LAMP1 and LAMP2 are confirmed substrates for FUT1 by targeted nanoLC-MS3 and MALDI-TOF analysis.\",\n      \"method\": \"FUT1 knockdown, targeted nanoLC-MS3 glycan analysis, MALDI-TOF, subcellular localization by imaging, mTORC1 activity measurement, autophagic flux assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed glycan modification combined with loss-of-function and multiple functional readouts, single lab\",\n      \"pmids\": [\"27560716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In Pompe disease (lysosomal glycogen storage disorder) fibroblasts, LAMP1 glycoprocessing is retarded (t1/2 = 25 min vs. 17 min in controls) and trafficking to lysosomes is markedly delayed (t1/2 = 200 min vs. 100 min). A proportion of newly synthesized LAMP1 (5-8%) is trafficked out of cells; the extracellular soluble form lacks the cytoplasmic tail, whereas a soluble lysosomal pool also lacks the tail, suggesting clipping from the membrane. LAMP1 turnover is slower in Pompe cells (t1/2 = 4.9 days vs. 1.6 days in controls).\",\n      \"method\": \"Pulse-chase metabolic labeling, subcellular fractionation, turnover assays, tail-domain characterization of extracellular LAMP1 forms\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative pulse-chase kinetics in disease vs. control fibroblasts, multiple trafficking readouts, single lab\",\n      \"pmids\": [\"10066386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Galectin-1 binds to LAMP1 (lysosome-associated membrane glycoprotein-1) as one of its major endogenous ligands in colon carcinoma cells, demonstrated by affinity chromatography of radiolabeled cell extracts on immobilized galectin-1 followed by immunoprecipitation from lactose-eluted material.\",\n      \"method\": \"Affinity chromatography on immobilized galectin-1, immunoprecipitation from lactose eluate, [3H]glucosamine radiolabeling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography with specificity control (lactose elution), single lab\",\n      \"pmids\": [\"7954433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cell surface LAMP1 on high-metastatic B16F10 melanoma cells facilitates lung metastasis primarily through its polyLacNAc (poly-N-acetyllactosamine) carbohydrates that bind galectin-3. LAMP1 is the major carrier of polyLacNAc on these cells. shRNA-mediated LAMP1 knockdown decreases surface LAMP1, reduces galectin-3 binding to cell surface, impairs spreading and motility on galectin-3, and significantly reduces experimental lung metastasis. Overexpression of a mutant LAMP1 (Y386A) with low polyLacNAc fails to augment galectin-3 binding or lung metastasis.\",\n      \"method\": \"shRNA inducible knockdown, lentiviral mutant overexpression, flow cytometry, experimental lung metastasis assay, galectin-3 binding assay, spreading/motility on ECM components\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with carbohydrate-deficient mutant, in vivo metastasis readout, single lab\",\n      \"pmids\": [\"25614122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Extracellular galectin-3 induces MMP9 expression via p38 MAPK pathway signaling through cell-surface LAMP1. LAMP1 is identified as the key mediator because shRNA knockdown of LAMP1 (which is the major carrier of polyLacNAc, the galectin-3 ligand) abolishes galectin-3-induced MMP9 upregulation via p38 MAPK.\",\n      \"method\": \"shRNA knockdown of LAMP1, signaling pathway inhibitors, RT-PCR/Western blot for MMP9\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — shRNA with pharmacological inhibitors placing LAMP1 in p38 MAPK signaling pathway, single lab\",\n      \"pmids\": [\"25739356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Drosophila Lamp1 is a bona fide ortholog of vertebrate LAMP1/LAMP2 but, unlike lamp1/lamp2 double-mutant mice, Lamp1-deficient flies are viable and do not show autophagy defects. However, Lamp1 deficiency increases the number of acidic organelles and causes defects in lipid metabolism, with elevated sterols and diacylglycerols, indicating a role for LAMP1 in lipid transport rather than autophagy in Drosophila.\",\n      \"method\": \"Drosophila Lamp1 mutant characterization, autophagy assays (LC3/Atg8a puncta, autophagic vacuoles), acidic organelle quantification (LysoTracker), lipid profiling\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal readouts in Drosophila model; divergence from mammalian function noted\",\n      \"pmids\": [\"35266854\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LAMP1 is a heavily N-glycosylated type I lysosomal membrane protein whose cytoplasmic YXXI tyrosine-based sorting motif mediates TGN-to-early endosome trafficking via AP-1 and AP-2 clathrin adaptors, with the spacing of this motif relative to the membrane being critical for proper sorting; its luminal Asn-linked glycans protect the polypeptide from lysosomal proteolysis; at the lysosomal membrane it stabilizes the polypeptide transporter TAPL and, in NK cells, is required for perforin trafficking to lytic granules (via AP-1 interaction) and for protection of NK cells from degranulation-associated self-damage through glycosylation-dependent suppression of perforin binding; LAMP1 also marks Ca2+-regulated lysosomal exocytosis (as seen in platelets, NK cells, and T. cruzi invasion), and at the cell surface its polyLacNAc carbohydrates engage galectin-3 to promote melanoma lung metastasis via p38 MAPK/MMP9 signaling; as a viral receptor, LAMP1's luminal domain (via a histidine-230 residue and a cholesterol-binding pocket) engages the Lassa virus GP1 histidine triad at acidic endosomal pH to elevate the pH threshold for membrane fusion and promote fusion pore dilation through its transmembrane domain.\"\n}\n```","stage2_raw":"","audit_flag":{"gene":"LAMP1","tier":"BEHAVIOR","verdict":"Model-behavior concern","subtype":"model_safety_refusal","uniprot_band":"rich","rules_fired":"R10","issue":"R10: API stop_reason='refusal' at stage2"},"evaluation":null}